Electricity Shocks Drug-Resistant Tumor Cells into Sensitivity

Action Points

Advise patients who ask that this preliminary in vitro study suggests that low-level electrical stimulation of a drug-resistant tumor will restore its sensitivity to chemotherapy.

Note that the value of the approach may be to reduce the amount of chemotherapy that is needed to overcome drug resistance, thereby reducing side effects and improving outcomes.

CLEVELAND, March 17 - Drug-resistant malignancies may be in for a shock if some experiments here pan out.

Exposing some drug-resistant tumor cells to low levels of electricity in vitro caused them to become more sensitive to chemotherapy, found researchers at the Cleveland Clinic Lerner College of Medicine.

Because electrical stimulation is already used in a variety of other settings in patients, "it seems possible that coupling electrical stimulation to current chemotherapy protocols will improve the efficacy of our therapeutic approach to neoplasms," Damir Janigro, Ph.D., and colleagues, wrote in the free-access online journal BMC Cancer.

The stimulation was applied to cancer cell lines that overexpress the MDR1 gene, which makes them resistant to drugs such as Adriamycin (doxorubicin), Dr. Janigro and colleagues said. MDR1 codes for drug transporter proteins, which are active against a wide range of drugs and are involved in extrusion of the drugs from the cell.

The researchers stimulated rodent and human cell lines (which over-expressed MDFR1 and its rodent homologs) with alternating current at 50 Hertz, with 10 seconds between pulses, for three days.

The stimulation was not enough to damage the cells, Dr. Janigro and colleagues found. The cells grew as fast in culture as non-stimulated controls.

However, it was enough to render them sensitive to Adriamycin, even at very low concentrations, they reported.

After stimulation, the cells were exposed to increasing concentrations of Adriamycin, ranging from one to eight micromoles, and the cell viability was measured by the release of adenylate kinase, which is rapidly released into culture media if cells are damaged or dying.

Even at the lowest concentration, the combination of the drug and electricity resulted in about a 30% increase in adenylate kinase release, compared to control cells. Adenylate kinase release increased in a dose-dependent fashion, the researchers found.

In a parallel experiment, the researchers treated the cells with a compound -- XR9576 -- that is known to inhibit MDR1 and then exposed the cells to Adriamycin.

At all dose levels, the combination of doxorubicin and electricity was comparable or better than the combination of the drug and inhibitor, as measured by adenylate kinase release, the researchers found.

"Had we used much higher concentration of XR9576, we would have achieved the same effect as with electrical stimulation," the researchers reported.

Analysis of stimulated cells showed that MDR1 expression was sharply decreased, and more concentrated in the cell cytosol, where it is non-functional. Dr. Janigro and colleagues hypothesized that the electricity slowed the release of MDR1 from the protein synthesis machinery in the cell.

A key limiting factor in any cancer therapy is the effect on healthy cells. The researchers showed that in normal astrocytes, stimulation did not result in increased uptake of Adriamycin. On the other hand, drug-resistant astrocytes that overexpressed MDR1, isolated from drug-refractory epileptic patients, showed the same pattern as drug-resistant tumor cells.

Also, since three days of electrical stimulation are needed to be effective -- several growth cycles for the tumor cells -- normal slow-growing cells "are practically unaffected by the exposure to the electric field," the researchers noted.

The value of an electrical-stimulation protocol, Dr. Janigro and colleagues said, is that it may make it possible to overcome drug-resistance with relatively low levels of chemotherapy, limiting both drug exposure and the associated side effects.

Reviewed by Zalman S. Agus, MD Emeritus Professor at the University of Pennsylvania School of Medicine